Coronary Microvascular Dysfunction and Major Adverse Cardiovascular Events in Patients With Ischemia and Non-obstructive Coronary Arteries: A Systematic Review

Coronary microvascular dysfunction (CMD) is a major pathophysiological substrate of ischemia with non-obstructive coronary arteries (INOCA), but available prognostic evidence remains heterogeneous in diagnostic methods, CMD definitions, outcome definitions, and reported effect measures. We conducted a systematic review with narrative synthesis of cohort studies examining the association between objectively verified CMD and major adverse cardiovascular events (MACE) in adults with INOCA. MEDLINE/PubMed, Embase, Cochrane CENTRAL, Scopus, and Web of Science were searched from inception to June 2026. Eight cohort studies representing eight unique countries met eligibility criteria and were included in the narrative synthesis. Two independent cohorts reported adjusted dichotomous hazard ratios for a CMD-versus-no-CMD contrast: HR 2.97, 95% CI 1.39-6.34 and HR 3.12, 95% CI 1.22-7.97, respectively. The largest and highest-quality included study (N=1,681, NOS 9/9) reported an adjusted hazard ratio for continuous coronary flow velocity reserve and was summarized narratively. The remaining studies reported non-comparable effect measures, exposure scales, adjustment levels, or overlapping cohorts. Because of heterogeneity in CMD definitions, diagnostic modalities, exposure scales, and effect-measure types, no meta-analysis was performed. Available observational evidence suggests that objectively identified CMD may be associated with increased MACE risk in patients with INOCA. Larger prospective studies using standardized CMD definitions, harmonized MACE outcomes, adequate follow-up, and consistently adjusted time-to-event analyses are needed.